1. Field of the Invention
The present invention relates to cytotoxic compounds, their use as antitumor agents, a novel process for their preparation, and intermediates produced thereby.
2. Background Art
Esperamicins and calichemicins belong to a class of extremely potent antitumor antibiotics isolated from microbial sources. Structure elucidation studies of the esperamicins and calichemicins were reported in J. Am. Chem. Soc., 1987, 109:3461-3462, and J. Am. Chem. Soc., 1987, 109:3464-3466, respectively. These antibiotics share a common aglycone core which contains a bicyclo[7.3.1]tridecane ring system with an allylic trisulfide side chain. ##STR1##
The proposed mechanism of action of these antibiotics involves, first, a bioreductive activation of the trisulfide to generate a thiol which adds intramolecularly to the .alpha.,.beta.-unsaturated enone. The resulting change of hybridization of the bridgehead carbon atom brings the two ends of the diynene portion into closer proximity to coalesce and form a benzene 1,4-diradical which is capable of abstracting a hydrogen atom from the sugar phosphate backbone of DNA to effect single and double stranded breakage.
The unique structure and mechanism of action of these compounds have engendered much interest in the synthesis of the bicyclic diynene core fragment. A number of strategies have been devised to achieve ring closure of a cyclohexyl compound bearing the requisite diynene fragment to form the 10-membered ring.
Kende, et al., (Tet. Lett., 1988, 29:4217-4220) treated 3,3-(1,2-ethylenedioxy)-5-(3-hexene-1,5-diynyl)-1-cyclohexenecarboxaldehyd e with lithium bis(trimethylsilyl)amide, followed by removal of the ethylenedioxy ketone protecting group to provide 8-hydroxy-bicyclo[7.3.1]tridec-4,9-diene.-2,6-diyn-11one.
Magnus, et al., (J. Am. Chem. Soc., 1988, 110:1626-1628) reported the preparation of 1-(TBSoxy)bicyclo[7.3.1]tridec-4-ene-2,6-diyn-10-one, dicobalt hexacarbonyl complex [TBS=t-butyldimethylsilyl] from 1,4-bis(TBSoxy)-4-(7-methoxy-3-heptene-1,5-diynyl)cyclohexene dicobalt hexacarbonyl complex upon treatment with titanium tetrachloride/diazabicyclo[2.2.2]octane (DABCO) at -78.degree. C. Decomplexation of the product, however, caused the molecule to collapse into the corresponding benzenoid compound.
Magnus, et al., (J. Am. Chem. Soc., 1988, 110:6921-6923) and Tomioka, et al., (Tet. Lett., 1989 30:851-854) reported the preparation of 1-(TBSoxy)bicyclo[7.3.1]tridec-4-ene-2,6-diyn-13-one (bicyclic ketone) from 1,6-bis-(TBSoxy)-6-(7-methoxy-heptene-1,5-diynyl)oyclohexene dicobalt hexacarbonyl complex upon treatment with titanium tetrachloride/DABCO, followed by decomplexation with iodine or trimethylamine oxide. Magnus, et al., further treated the bicyclic ketone product with potassium hexamethyldisilazane (KHMDS) and phenylselenium chloride to form the .alpha.-phenylselenide which, upon oxidation with hydrogen peroxide, provided 1-(TBSoxy)-bicyclo[7.3.1]tridec-4,9-diene-2,6-diyn-13one (bicyclic enone). This latter product was also obtained as a minor product when the TBS enol ether of the bicyclic ketone was oxidized with selenium dioxide (Magnus, et al., Tet. Lett., 1989, 30:3637-3640).
Danishefsky, et al., (J. Am. Chem. Soc., 1988, 10:6890-6891) reported the preparation of 1-(TBSoxy)-8-hydroxy-11-methoxy-bicyclo[7.3.1]tridec-4,9,11-triene-2,6-diy ne 13-spiroethylene epoxide from 3-methoxy-5-(TBSoxy)-5-(3-hexene-1,5-diynyl)-1,6-cyclohexadienecarboxaldeh yde 6-spiro ethylene epoxide upon treatment with base. The product was further elaborated to provide inter alia 1,8-dihydroxybicyclo[7.3.1]tridec-4,9-diene-2,6-diyn-11,13-dione and the corresponding 11-ethylene ketal, and 1,8-dihydroxy-bicyclo[7.3.1]tridec-4-ene-2,6-diyn-11,13-dione. This latter compound was shown to cleave DNA in vitro (J. Org. Chem., 1989, 54:2781-2783 and J. Am. Chem. Soc., 1989, 111:7638-7641).
Magnus, et al., (J. Org. Chem., 1990, 55(6):1709-1711) reported the preparation of 8-hydroxy-1-TBSoxybicyclo[7.3.1]tridec-4-ene-2,6-diyn-13-one by treating 6-TBSoxy-6-(7-oxo-3-hexene-1,5-diynyl)cyclohexanone dicobalt complex with dibutylboron triflate/DABCO to effect ring closure, followed by N-methyl-morpholine oxide to remove the cobalt carbonyl group.
Danishefsky, et al., (J. Am. Chem. Soc., 1990, 112:3253-3255) reported the total synthesis of dl-calicheamicinone.
The known methods for ring closure either require the use of cumbersome precursors which are difficult to prepare, or they yield bicyclic diynenes lacking certain key functionalities. The process of the present invention circumvents these problems and provides a highly efficient route to bicyclic diynenes with multiple key functionalities. Furthermore, the present process results in the formation of a single pair of diastereomers and allows the introduction of the 8-hydroxy group having the same relative stereochemical configuration as the 8-hydroxy group of the esperamicin aglycone.